1. Field of the Invention
The present invention relates to a method for treating liver injury. More particularly, the present invention is concerned with a method for treating liver injury, which comprises administering to a patient suffering from liver injury a composition comprising a thrombomodulin as an active ingredient and at least one pharmaceutically acceptable carrier. The method of the present invention is very effective for ameliorating liver injury, such as fulminant hepatitis and hepatic veno-occlusive disease (VOD) which is likely to frequently occur after bone marrow transplantation.
2. Prior Art
Liver is the largest single organ in a living body, and is the principal site of saccharometabolism, protein metabolism and lipid metabolism. In addition, drug metabolism, detoxification, storage of substances, and synthesis of proteins, such as a protein participating in blood coagulation, are also important functions of the liver. Thus, the liver is an essential organ to the maintenance of homeostasis and life. In a physiological view, the above-mentioned functions are the result of individual actions or interactions of the cells which constitute the liver, such as liver parenchyma cells, Kupffer cells and sinusoid endothelial cells. As mentioned above, the liver is an essential organ to a living body. Therefore, once a living body suffers liver injury due to the invasion of a virus from the exterior, the intake of alcohol, or the like, the body is likely to fall into a serious condition.
With respect to liver injury, various causes can be mentioned, for example, toxic substances which directly damage liver parenchyma cells and the metabolism thereof; active oxygen and peroxylipids which are generated during the metabolism of a substance, such as an alcohol; microcirculation injury resulting from a local progress of blood coagulation; and an autoimmunity which is induced by the infection with a hepatitis virus, such as hepatitis B virus.
A number of types of compositions for treating liver injury ascribed to the above-mentioned various causes have been used. However, no therapeutically definitive composition for treating liver injury has yet been developed. This fact is described in detail in the publication, "The Journal of Practical Pharmacy, 41(11) 1-53 (1990)". For example, this publication describes that the majority of parenteral fluids containing amino acids in specific formulations and of vitamin supplements serve only as an auxiliary treatment, such as treatment for supplementing the shortage of essential nutrients and vitamins which is caused by the depression of the metabolisms in liver, and also describes that, with respect to antidotes, representative examples of which include SH compounds, such as glutathione and thiopronine, their detoxification effects are uncertain. Further, according to this publication, various drugs having therapeutic effects against liver injury, such as anti-inflammatory or immunomodulating drugs (e.g., an adrenal cortical hormone, glycylrhizin, azathioprine and the like); protein synthesis accelerators (e.g., malothilate and the like); and interferons having antiviral activity, are known to cause serious side effects, such as hepatic disorder, hypoaldosteronism, agranulocytosis, icterus and cardiomyopathy.
Incidentally, a thrombomodulin is a substance which has the ability to specifically bind to thrombin to inhibit blood coagulation activity of the thrombin, and to promote the activation of protein C by thrombin. Thus, a thrombomodulin is known to have a strong anti-blood coagulation activity. By animal experiments, it has been demonstrated that the thrombomodulin is effective for treatment and prevention of diseases which accompany the progress of blood coagulation, such as thrombosis and disseminated intravascular coagulation (DIC) see K. Gomi et. al., Blood, 75, 1396-1399 (1990)!.
The thrombomodulin is a glycoprotein which is present on the membrane of vascular endothelial cells. Recently, a thrombomodulin is produced by genetic engineering techniques. The cloning of human thrombomodulin cDNA has been reported (see S. Yamamoto et. al, International Application Publication No. WO88/05053), and it has been elucidated that the human thrombomodulin is a membrane-bound protein composed of domain 1 (N-terminal domain), domain 2 (EGF domains), and domain 3 (O-glycosylation site rich domain), wherein domains 1 to 3 are extracellular domains, domain 4 (transmembrane domain) is a hydrophobic region, and domain 5 is an intracellular domain see The EMBO Journal, 6(7), 1891-1897 (1987)!, wherein domains 1 to 5 are arranged in that order starting from the N-terminus thereof. Further, it is known that the minimum active unit of the thrombomodulin is present in the 4th to 6th EGF domains among the six EGF domains constituting domain 2, and that a peptide fragment comprising these 4th to 6th EGF domains of the thrombomodulin is also considered to be effective for the treatment of diseases which accompany the progress of blood coagulation, such as thrombosis and DIC see M. Zushi et. al., J. Biol. Chem., 266, 19886-19889 (1991)!.
However, no reports have been found with respect to the pharmacological effects of a thrombomodulin on diseases other than diseases which accompany the progress of blood coagulation, such as thrombosis and DIC.